| Abstract: |
Sensitivity of human soft tissue sarcoma (STS) cells to methotrexate, doxorubicin, and paclitaxel was examined after cells were pretreated with CH-11, an agonistic anti-Fas antibody. A subtoxic dose (6 ng/ml) of CH-11 sensitized STS cells but not normal fibroblast cells to these anticancer drugs. CH-11 increased cytochrome c release and consequent activation of caspase-9, independent of caspase-8 and increased p38 activation. Addition of SB203580, a specific inhibitor of p38, resulted in a decrease in activation of this kinase and abrogation of enhanced chemosensitivity (doxorubicin and paclitaxel) by CH-11. These results demonstrate that stimulation of the Fas pathway by a subtoxic dose of a Fas agonist can selectively enhance sensitivity of STS cells to certain chemotherapeutic agents through activation of p38. © 2002 American Association for Cancer Research. |
| Keywords: |
signal transduction; mitogen activated protein kinase; doxorubicin; dose response; antineoplastic agents; pyridines; paclitaxel; flow cytometry; antineoplastic agent; metabolism; cell death; cell cycle; mitogen activated protein kinase p38; fas antigen; antineoplastic agents, phytogenic; enzyme activation; pathology; dose-response relationship, drug; tumor cells, cultured; caspase; caspases; time; time factors; sarcoma; blotting, western; cell culture; western blotting; drug derivative; caspase 9; antibiotics, antineoplastic; mitogen-activated protein kinases; antineoplastic antibiotic; cell separation; soft tissue neoplasms; soft tissue tumor; imidazoles; imidazole derivative; pyridine derivative; cytochrome c; antigens, cd95; p38 mitogen-activated protein kinases; chalcones; 4 (4 fluorophenyl) 2 (4 methylsulfinylphenyl) 5 (4 pyridyl)imidazole; humans; human; article; casp9 protein, human; 4 dimethylamino 3',4' dimethoxychalcone; 4-dimethylamino-3',4'-dimethoxychalcone; chalcone; chalcone derivative; cytochrome c group
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